Publications by authors named "Xianlin Han"

264 Publications

Mass Spectrometry-Based Shotgun Lipidomics for Cancer Research.

Adv Exp Med Biol 2021 ;1280:39-55

Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA.

Shotgun lipidomics is an analytical approach for large-scale and systematic analysis of the composition, structure, and quantity of cellular lipids directly from lipid extracts of biological samples by mass spectrometry. This approach possesses advantages of high throughput and quantitative accuracy, especially in absolute quantification. As cancer research deepens at the level of quantitative biology and metabolomics, the demand for lipidomics approaches such as shotgun lipidomics is becoming greater. In this chapter, the principles, approaches, and some applications of shotgun lipidomics for cancer research are overviewed.
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http://dx.doi.org/10.1007/978-3-030-51652-9_3DOI Listing
April 2021

Lipid Metabolism and Lipidomics Applications in Cancer Research.

Adv Exp Med Biol 2021 ;1316:1-24

Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA.

Lipids are the critical components of cellular and plasma membrane, which constitute an impermeable barrier of cellular compartments, and play important roles on numerous cellular processes including cell growth, proliferation, differentiation, and signaling. Alterations in lipid metabolism have been implicated in the development and progression of cancers. However, unlike other biomolecules, the diversity in the structures and characteristics of lipid species results in the limited understanding of their metabolic alterations in cancers. Lipidomics is an emerging discipline that studies lipids in a large scale based on analytical chemistry principles and technological tools. Multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) uses direct infusion to avoid difficulties from alterations in concentration, chromatographic anomalies, and ion-pairing alterations to improve resolution and achieve rapid and accurate qualitative and quantitative analysis. In this chapter, lipids and lipid metabolism relevant to cancer research are introduced, followed by a brief description of MDMS-SL and other shotgun lipidomics techniques and some applications for cancer research.
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http://dx.doi.org/10.1007/978-981-33-6785-2_1DOI Listing
March 2021

Lipidomics Revealed Aberrant Metabolism of Lipids Including FAHFAs in Renal Tissue in the Progression of Lupus Nephritis in a Murine Model.

Metabolites 2021 Feb 27;11(3). Epub 2021 Feb 27.

Barshop Institute for Longevity and Aging Studies, San Antonio, TX 78229, USA.

Lupus nephritis (LN) is an inflammatory renal disease of patients with systemic lupus erythematosus with lots of immune complexes deposited in kidneys. Accumulated studies have demonstrated the close relationships among dyslipidaemia, inflammation, and autoimmune response, and oxidative stress in the patients. Lipids play numerous important roles in biological process and cellular functions. Herein, shotgun lipidomics was employed to quantitatively analyze cellular lipidomes in the renal tissue of MRL/lpr mice in the progression of LN (including pre-LN and LN state) with/without treated with glucocorticoids (GCs). The levels of cytokines (i.e., TNF-α (Tumor necrosis factor alpha) and IL-6 (Interleukin 6)) in the serum were measured by ELISA (enzyme-linked immunosorbent assay) kits. Renal histopathological changes and C3 deposition in the glomeruli of the mice were also determined. Lipidomics analysis revealed that the ectopic fat deposition and the aberrant metabolism of lipids that were relevant to oxidative stress (e.g., 4-hydroxyalkenal, ceramide, lysophospholipid species, etc.) always existed in the development of LN. Moreover, the anti-inflammatory FAHFA (fatty acid ester of hydroxyl fatty acid) species in the kidney tissue could largely reflect the severity of LN. Thus, they were a potential early biomarker for LN. In addition, the study also revealed that treatment with GCs could prevent the progression of LN, but greatly aggravate the aberrant metabolism of the lipids, particularly when used for a long time.
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http://dx.doi.org/10.3390/metabo11030142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996882PMC
February 2021

Alterations in acylcarnitines, amines, and lipids inform about the mechanism of action of citalopram/escitalopram in major depression.

Transl Psychiatry 2021 Mar 2;11(1):153. Epub 2021 Mar 2.

Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, Durham, NC, USA.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines-including arginine, proline, and methionine sulfoxide-were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD≤ 7) and those who gained no meaningful benefits (<30% reduction in HRSD). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics-including acylcarnitine metabolism, transport, and its link to β-oxidation-and lipid membrane remodeling may play roles in SSRI treatment response.
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http://dx.doi.org/10.1038/s41398-020-01097-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925685PMC
March 2021

Overview of Lipidomic Analysis of Triglyceride Molecular Species in Biological Lipid Extracts.

J Agric Food Chem 2021 Feb 19. Epub 2021 Feb 19.

Department of Medicine-Nephrology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.

Triglyceride (TG) is a class of neutral lipids, which functions as an energy storage depot and is important for cellular growth, metabolism, and function. The composition and content of TG molecular species are crucial factors for nutritional aspects in food chemistry and are directly associated with several diseases, including atherosclerosis, diabetes, obesity, stroke, etc. As a result of the complexities of aliphatic moieties and their different connections/locations to the glycerol backbone in TG molecules, accurate identification of individual TG molecular species and quantitative assessment of TG composition and content are particularly challenging, even at the current stage of lipidomics development. Herein, methods developed for analysis of TG species, such as liquid chromatography-mass spectrometry with a variety of columns and different mass spectrometric techniques, shotgun lipidomics approaches, and ion-mobility-based analysis, are reviewed. Moreover, the potential limitations of the methods are discussed. It is our sincere hope that the overviews and discussions can provide some insights for researchers to select an appropriate approach for TG analysis and can serve as the basis for those who would like to establish a methodology for TG analysis or develop a new method when novel tools become available. Biologically accurate analysis of TG species with an enabling method should lead us toward improving the nutritional quality, revealing the effects of TG on diseases, and uncovering the underlying biochemical mechanisms related to these diseases.
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http://dx.doi.org/10.1021/acs.jafc.0c07175DOI Listing
February 2021

Emergency laparoscopic pancreatoduodenectomy as treatment for pancreatic head cancer-induced acute gastrointestinal hemorrhage, safe or not?

Hepatobiliary Surg Nutr 2021 Jan;10(1):146-148

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

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http://dx.doi.org/10.21037/hbsn-20-613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867733PMC
January 2021

High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance.

Nat Commun 2021 01 11;12(1):213. Epub 2021 Jan 11.

James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA.

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.
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http://dx.doi.org/10.1038/s41467-020-20500-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801461PMC
January 2021

Radical antegrade modular pancreatosplenectomy (RAMPS) versus conventional distal pancreatosplenectomy (CDPS) for left-sided pancreatic ductal adenocarcinoma.

Surg Today 2021 Jan 3. Epub 2021 Jan 3.

Department of General Surgery, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.

Purpose: The insufficient clearance of regional lymph nodes and unsatisfactory R0 resection rate may result in the metastasis of left-sided pancreatic ductal adenocarcinoma (PDAC) after conventional distal pancreatosplenectomy (CDPS). Radical antegrade modular pancreatosplenectomy (RAMPS) was designed to achieve R0 resection more successfully with better lymph-node clearance; however, there is still insufficient evidence of its short- and long-term results to confirm its superiority. We conducted this study to compare the efficiency of these two procedures.

Methods: The subjects of this retrospective analysis were 103 patients with left-sided PDAC who underwent either RAMPS (n = 46) or CDPS (n = 57). We assessed perioperative data and surgical information and used univariate and multivariate analyses to identify prognostic factors for survival.

Results: There were no significant differences in baseline data between the groups. RAMPS was associated with a significantly shorter hospital stay (12.11 days vs. 22.98 days; P < 0.001), and significantly less blood loss (451.09 ml vs. 764.04 ml, P = 0.002), as well as a significantly lower rate of blood transfusion (15.22% vs. 33.33%, P = 0.035). RAMPS and CDPS had comparable perioperative complication rates. Moreover, RAMPS achieved more effective lymph-node retrieval (17.87 vs. 10.23; P < 0.001). The RAMPS group had a higher overall survival (OS) rate (28.73 months vs. 18.30 months; P = 0.003) and a higher disease-free survival (DFS) rate (21.97 months vs. 9.40 months; P < 0.001).

Conclusion: RAMPS achieved better survival and surgical outcomes than CDPS for patients with left-sided PDAC.
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http://dx.doi.org/10.1007/s00595-020-02203-3DOI Listing
January 2021

Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease.

Mol Metab 2021 Mar 23;45:101154. Epub 2020 Dec 23.

Division of Diabetes, University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, TX, USA. Electronic address:

Objective: Insulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), but the etiological role of these processes in disease progression remains unclear. Here we investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation.

Methods: Hepatic insulin sensitivity, endogenous glucose production, and mitochondrial metabolic fluxes were determined in wild-type, obese (ob/ob) and pioglitazone-treatment obese mice using a combination of radiolabeled tracer and stable isotope NMR approaches. Mechanistic studies of pioglitazone action were performed in isolated primary hepatocytes, whilst molecular hepatic lipid species were profiled using shotgun lipidomics.

Results: Livers from obese, insulin-resistant mice displayed augmented mitochondrial content and increased tricarboxylic acid cycle (TCA) cycle and pyruvate dehydrogenase (PDH) activities. Insulin sensitization with pioglitazone mitigated pyruvate-driven TCA cycle activity and PDH activation via both allosteric (intracellular pyruvate availability) and covalent (PDK4 and PDP2) mechanisms that were dependent on PPARγ activity in isolated primary hepatocytes. Improved mitochondrial function following pioglitazone treatment was entirely dissociated from changes in hepatic triglycerides, diacylglycerides, or fatty acids. Instead, we highlight a role for the mitochondrial phospholipid cardiolipin, which underwent pathological remodeling in livers from obese mice that was reversed by insulin sensitization.

Conclusion: Our findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity-associated disease.
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http://dx.doi.org/10.1016/j.molmet.2020.101154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811046PMC
March 2021

Oxidative stress-induced aberrant lipid metabolism is an important causal factor for dysfunction of immunocytes from patients with systemic lupus erythematosus.

Free Radic Biol Med 2021 Feb 19;163:210-219. Epub 2020 Dec 19.

College of Basic Medical Sciences, Zhejiang Chinese Medical University, 548 Bingwen Road, Hangzhou, Zhejiang, 310053, China. Electronic address:

There exist close relationships among oxidative stress, dyslipidaemia, inflammation, and autoimmune response in patients with systemic lupus erythematosus (SLE). Dysfunction and/or dysregulation of immunocytes is one of the major characteristics of SLE pathogenesis. Lipids play many important roles in biological processes and cellular functions. We hypothesized that oxidative stress-induced aberrant lipid metabolism and integrity presented in immunocytes is one of the early events in patients, thereby leading to enhanced production of IgG autoantibodies and cytokines. Herein, shotgun lipidomics was employed for quantitative analysis of cellular lipidomes in peripheral blood mononuclear cells (PBMC) both freshly isolated from SLE patients and cultured with treatment. The levels of IgG autoantibodies and cytokines in cell culture media and serum samples from lupus-prone mice treated with a natural, powerful antioxidant isotonix OPC-3 were measured by ELISA kits. IgG antibody deposition in glomeruli of the mice was determined by immunofluorescence analysis. Lipidomics analysis of PBMC from 33 SLE patients and 28 healthy controls revealed aberrant lipid metabolism in PBMC from the patients. The changes included significantly reduced plasmalogens, markedly increased lysophospholipids, altered phosphatidylserines, and accumulated 4-hydroxyalkenals. These alterations of lipids in SLE PBMC could be significantly corrected after cultured with the antioxidant in vitro. Parallel to the IgG antibody deposition in glomeruli, the concentrations of cytokines (i.e., IL-10, IL-6, and TNF-α) and autoantibodies (e.g., IgG antiphospholipid and anti-dsDNA antibodies) in culture medium and serum samples from the mice after treatment with the antioxidant were also significantly reduced compared with those of the SLE group. The results clearly demonstrated that correction of the aberrant lipid metabolism led to inhibition of the autoimmune reactions of PBMC after reduction of the increased oxidative stress. The current study also revealed potential drug treatment of SLE with lesser adverse effects through reducing the aberrant lipid metabolism with an effective antioxidant.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.12.006DOI Listing
February 2021

The promoting effects of hsa_circ_0050102 in pancreatic cancer and the molecular mechanism by targeting miR-1182/NPSR1.

Carcinogenesis 2020 Dec 8. Epub 2020 Dec 8.

Department of General Surgery, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China.

Pancreatic cancer is one of the most lethal tumors across the world with an overall 5-year survival rate of 9%, and great efforts have been devoted in early diagnosis and treatment in the past decades. Competing endogenous RNAs are novel and specific regulatory mechanisms of gene expression, and researches have indicated its important roles in tumor regulation. In this study, we explored the circ-0050102 expression in pancreatic cancer and its impacts on tumor malignant phenotypes, and further investigated the correlations among circ-0050102, miR-1182 and NPSR1. Results of real-time quantitative PCR showed that circ-0050102 expressed higher in pancreatic cancers compared with that in adjacent normal tissues. In cell functional experiment, down-regulation of circ-0050102 could suppress cell proliferation, migration and invasion ability, boost cell apoptosis and arrest cell cycle in both PANC-1 and CFPAC-1 cells. Furthermore, allogeneic transplantation in nude mice was performed and results showed that inhibition of circ-0050102 could slow down tumor formation in vivo. Mechanism research suggested that circ-0050102 could down-regulate miR-1182 while miR-1182 couldn't influence expression of circ-0050102, and miR-1182 could directly target at NPSR1 and suppressed it. Moreover, circ-0050102 could reverse the effects of si-NPSR1 on pancreatic cancer cells. In conclusion, we identified that circ-0050102 played an important role in promoting pancreatic cancer by regulating the miR-1182 / NPSR1 pathway.
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http://dx.doi.org/10.1093/carcin/bgaa130DOI Listing
December 2020

A Lipidomics View of Circadian Biology.

Methods Mol Biol 2021 ;2130:157-168

Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.

Lipidomics approaches provide quantitative characterization of hundreds of lipid species from biological samples. Recent studies highlight the value of these methods in studying circadian biology, and their potential goes far beyond studying lipid metabolism per se. For example, lipidomics analyses of subcellular compartments can be used to determine daily rhythmicity of different organelles and their intracellular dynamics. In this chapter we describe in detail the procedure for around the clock shotgun lipidomics, from sample preparation to bioinformatics analyses. Sample preparation includes biochemical fractionation of nuclei and mitochondria from mouse liver harvested throughout the day. Lipid content is determined and quantified, in unbiased manner and with wide coverage, using multidimensional mass spectrometry shotgun lipidomics (MDMS-SL). Circadian parameters are then determined with nonparametric statistical tests. Overall, the approach described herein is applicable for various animal models, tissues, and organelles, and is expected to yield new insight on various aspects of circadian biology and lipid metabolism.
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http://dx.doi.org/10.1007/978-1-0716-0381-9_12DOI Listing
March 2021

Hepatocyte-specific PKCβ deficiency protects against high-fat diet-induced nonalcoholic hepatic steatosis.

Mol Metab 2021 02 30;44:101133. Epub 2020 Nov 30.

Department of Biological Chemistry and Pharmacology, Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address:

Objective: Nonalcoholic hepatic steatosis, also known as fatty liver, is a uniform response of the liver to hyperlipidic-hypercaloric diet intake. However, the post-ingestive signals and mechanistic processes driving hepatic steatosis are not well understood. Emerging data demonstrate that protein kinase C beta (PKCβ), a lipid-sensitive kinase, plays a critical role in energy metabolism and adaptation to environmental and nutritional stimuli. Despite its powerful effect on glucose and lipid metabolism, knowledge of the physiological roles of hepatic PKCβ in energy homeostasis is limited.

Methods: The floxed-PKCβ and hepatocyte-specific PKCβ-deficient mouse models were generated to study the in vivo role of hepatocyte PKCβ on diet-induced hepatic steatosis, lipid metabolism, and mitochondrial function.

Results: We report that hepatocyte-specific PKCβ deficiency protects mice from development of hepatic steatosis induced by high-fat diet, without affecting body weight gain. This protection is associated with attenuation of SREBP-1c transactivation and improved hepatic mitochondrial respiratory chain. Lipidomic analysis identified significant increases in the critical mitochondrial inner membrane lipid, cardiolipin, in PKCβ-deficient livers compared to control. Moreover, hepatocyte PKCβ deficiency had no significant effect on either hepatic or whole-body insulin sensitivity supporting dissociation between hepatic steatosis and insulin resistance.

Conclusions: The above data indicate that hepatocyte PKCβ is a key focus of dietary lipid perception and is essential for efficient storage of dietary lipids in liver largely through coordinating energy utilization and lipogenesis during post-prandial period. These results highlight the importance of hepatic PKCβ as a drug target for obesity-associated nonalcoholic hepatic steatosis.
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http://dx.doi.org/10.1016/j.molmet.2020.101133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785956PMC
February 2021

Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer's disease.

Nat Commun 2020 11 10;11(1):5698. Epub 2020 Nov 10.

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer's disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation.
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http://dx.doi.org/10.1038/s41467-020-19473-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655942PMC
November 2020

Early disruption of nerve mitochondrial and myelin lipid homeostasis in obesity-induced diabetes.

JCI Insight 2020 11 5;5(21). Epub 2020 Nov 5.

Barshop Institute for Longevity and Aging Studies and.

Diabetic neuropathy is a major complication of diabetes. Current treatment options alleviate pain but do not stop the progression of the disease. At present, there are no approved disease-modifying therapies. Thus, developing more effective therapies remains a major unmet medical need. Seeking to better understand the molecular mechanisms driving peripheral neuropathy, as well as other neurological complications associated with diabetes, we performed spatiotemporal lipidomics, biochemical, ultrastructural, and physiological studies on PNS and CNS tissue from multiple diabetic preclinical models. We unraveled potentially novel molecular fingerprints underlying nerve damage in obesity-induced diabetes, including an early loss of nerve mitochondrial (cardiolipin) and myelin signature (galactosylceramide, sulfatide, and plasmalogen phosphatidylethanolamine) lipids that preceded mitochondrial, myelin, and axonal structural/functional defects; started in the PNS; and progressed to the CNS at advanced diabetic stages. Mechanistically, we provided substantial evidence indicating that these nerve mitochondrial/myelin lipid abnormalities are (surprisingly) not driven by hyperglycemia, dysinsulinemia, or insulin resistance, but rather associate with obesity/hyperlipidemia. Importantly, our findings have major clinical implications as they open the door to novel lipid-based biomarkers to diagnose and distinguish different subtypes of diabetic neuropathy (obese vs. nonobese diabetics), as well as to lipid-lowering therapeutic strategies for treatment of obesity/diabetes-associated neurological complications and for glycemic control.
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http://dx.doi.org/10.1172/jci.insight.137286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710310PMC
November 2020

is associated with longevity independent of Alzheimer's disease.

Elife 2020 10 19;9. Epub 2020 Oct 19.

Department of Neuroscience, Mayo Clinic, Jacksonville, United States.

Although the ε2 allele of apolipoprotein E () benefits longevity, its mechanism is not understood. The protective effects of the 2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound effects on longevity. Herein, we showed that the association between and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models. Notably, was associated with preserved activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate that can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of -mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.
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http://dx.doi.org/10.7554/eLife.62199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588231PMC
October 2020

Leptin Receptors in RIP-Cre Neurons Mediate Anti-dyslipidemia Effects of Leptin in Insulin-Deficient Mice.

Front Endocrinol (Lausanne) 2020 23;11:588447. Epub 2020 Sep 23.

Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States.

Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of whole-body metabolism such as glucose and lipid metabolism, even without insulin. Central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms, including improvements of dyslipidemia. However, the specific neurons that regulate anti-dyslipidemia effects of leptin remain unidentified. Here we report that leptin receptors (LEPRs) in neurons expressing Cre recombinase driven by a short fragment of a promoter region of gene (RIP-Cre neurons) are required for central leptin signaling to reverse dyslipidemia, thereby hyperglycemia in insulin-deficient mice. Ablation of LEPRs in RIP-Cre neurons completely blocks glucose-lowering effects of leptin in insulin-deficient mice. Further investigations reveal that insulin-deficient mice lacking LEPRs in RIP-Cre neurons (RIP-Cre mice) exhibit greater lipid levels in blood and liver compared to wild-type controls, and that leptin injection into the brain does not suppress dyslipidemia in insulin-deficient RIP-Cre mice. Leptin administration into the brain combined with acipimox, which lowers blood lipids by suppressing triglyceride lipase activity, can restore normal glycemia in insulin-deficient RIP-Cre mice, suggesting that excess circulating lipids are a driving-force of hyperglycemia in these mice. Collectively, our data demonstrate that LEPRs in RIP-Cre neurons significantly contribute to glucose-lowering effects of leptin in an insulin-independent manner by improving dyslipidemia.
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http://dx.doi.org/10.3389/fendo.2020.588447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538546PMC
September 2020

Comparison of minimal invasive versus open radical antegrade modular pancreatosplenectomy (RAMPS) for pancreatic ductal adenocarcinoma: a single center retrospective study.

Surg Endosc 2020 Oct 8. Epub 2020 Oct 8.

Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1, Shuai Fu Yuan, Dongcheng District, Beijing, 100730, China.

Introduction: Radical antegrade modular pancreatosplenectomy (RAMPS) was proposed a decade ago with the aim to achieve higher R0 tangential margin and radical N1 lymph node resection for left-sided pancreatic adenocarcinoma (PDAC), which has been widely accepted worldwide at present. Laparoscopic RAMPS (Lap-RAMPS) has been attempted for PDAC during last several years, however, no outcomes evaluation by comparison between laparoscopic vs open RAMPS has been reported yet.

Materials And Methods: From August, 2012 to March, 2018, patients undergoing open or lap-RAMPS for the diagnosis of left-sided PDAC were reviewed from a prospective database. Patients excluded if they were related with combined organs or vessels resection, systematic metastasis as well as conversion from open RAMPS to lap RAMPS. The surgical and oncologic outcomes were compared.

Results: A total of 48 PDAC patients were enrolled (25 underwent lap-RAMPS and 23 underwent open-RAMPS). There were no significant differences in demographic or perioperative morbidity. In the lap-RAMPS group, R0 transection margin and retroperitoneal margin were both achieved in 23 of 25 patients (92%). In the open RAMPS group, R0 transection margin was achieved in 21 of 23 patients (91.3%), R0 retroperitoneal margin was 22 of 23 patients (95.65%). There were no differences in pathological examinations. The number of lymph node (LN) retrieved between lap-RAMPS and open- RAMPS group was not significant difference (15.84 vs 18.22; P = 0.268). Median disease-free survival (DFS) was analogous in two groups (18.11 m vs 20.00 m, P = 0.999). Median overall survival (OS) was 24.53 m in lap-RAMPS group and 28.73 m in the open-RAMPS group (P = 0.633).

Conclusions: Lap-RAMPS is technically feasible, and has comparable long-term oncological outcome with open-RMAPS.
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http://dx.doi.org/10.1007/s00464-020-07938-1DOI Listing
October 2020

RECOGNITION AND AVOIDANCE OF ION SOURCE-GENERATED ARTIFACTS IN LIPIDOMICS ANALYSIS.

Mass Spectrom Rev 2020 Sep 30. Epub 2020 Sep 30.

Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.

Lipid research is attracting more and more attention as various key roles and novel biological functions of lipids have been demonstrated and discovered in the organism. Mass spectrometry (MS)-based lipidomics approaches are the most powerful and effective tools for analysis of cellular lipidomes with very high sensitivity and specificity. However, the artifacts generated from in-source fragmentation are always present in all kinds of ion sources, even soft ionization techniques (i.e., electrospray ionization and matrix-assisted laser desorption/ionization [MALDI]). These artifacts can cause many problems for lipidomics, especially when the fragment ions correspond to/are isomeric species of other endogenous lipid species in complex biological samples. These commonly observed artifacts could lead to misannotation, false identification, and consequently, incorrect attribution of phenotypes, and will have negative impact on any MS-based lipidomics research including but not limited to biomarker discovery, drug development, etc. Liquid chromatography-MS, shotgun lipidomics, and MALDI-MS imaging are three representative lipidomics approaches in which ion source-generated artifacts are all manifested and are comprehensively summarized in this article. The strategies on how to avoid/reduce the artifacts of in-source fragmentation on lipidomics analysis are also discussed in detail. We believe that with the recognition and avoidance of ion source-generated artifacts, MS-based lipidomics approaches will provide better accuracy on comprehensive analysis of biological samples and will make greater contribution to the research on metabolism and translational/precision medicine (collectively termed functional lipidomics). © 2020 John Wiley & Sons Ltd. Mass Spec Rev.
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http://dx.doi.org/10.1002/mas.21659DOI Listing
September 2020

Docosahexaenoic Acid (DHA) Supplementation Alters Phospholipid Species and Lipid Peroxidation Products in Adult Mouse Brain, Heart, and Plasma.

Neuromolecular Med 2021 03 14;23(1):118-129. Epub 2020 Sep 14.

Department of Chemistry, University of Missouri, 125 Chemistry Bldg., Columbia, MO, 65211, USA.

The abundance of docosahexaenoic acid (DHA) in phospholipids in the brain and retina has generated interest to search for its role in mediating neurological functions. Besides the source of many oxylipins with pro-resolving properties, DHA also undergoes peroxidation, producing 4-hydroxyhexenal (4-HHE), although its function remains elusive. Despite wide dietary consumption, whether supplementation of DHA may alter the peroxidation products and their relationship to phospholipid species in brain and other body organs have not been explored sufficiently. In this study, adult mice were administered a control or DHA-enriched diet for 3 weeks, and phospholipid species and peroxidation products were examined in brain, heart, and plasma. Results demonstrated that this dietary regimen increased (n-3) and decreased (n-6) species to different extent in all major phospholipid classes (PC, dPE, PE-pl, PI and PS) examined. Besides changes in phospholipid species, DHA-enriched diet also showed substantial increases in 4-HHE in brain, heart, and plasma. Among different brain regions, the hippocampus responded to the DHA-enriched diet showing significant increase in 4-HHE. Considering the pro- and anti-inflammatory pathways mediated by the (n-6) and (n-3) polyunsaturated fatty acids, unveiling the ability for DHA-enriched diet to alter phospholipid species and lipid peroxidation products in the brain and in different body organs may be an important step forward towards understanding the mechanism(s) for this (n-3) fatty acid on health and diseases.
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http://dx.doi.org/10.1007/s12017-020-08616-0DOI Listing
March 2021

Analysis of monohexosyl alkyl (alkenyl)-acyl glycerol in brain samples by shotgun lipidomics.

Anal Chim Acta 2020 Sep 24;1129:143-149. Epub 2020 Jul 24.

Barshop Institute for Longevity and Aging Studies, San Antonio, TX, 78229, USA; Department of Medicine - Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. Electronic address:

Lipid species possess very different structures, leading to their very diversified cellular functions in biological systems. Lipidomics represents a powerful technology for deep analysis of hundreds to thousands of intact lipid molecular species. In the current study, a cluster of unknown ion peaks was displayed when we profiled cerebroside species in rat spinal cord samples by neutral loss scan of 162 Da in the positive ion mode using a multi-dimensional mass spectrometry-based shotgun lipidomics strategy. In order to identify the structural identities of these unknown ion peaks, MS and MS analyses of these ions were performed by high mass resolution mass spectrometry. Extensive lines of evidence allowed us to identify that these unknown ion peaks were monohexosyl alkyl-acyl glycerol (HAAG) species, including their sn-positional isomers and alkyl-acyl compositional isomers. We also applied the developed method to identify and quantify HAAG species present in a variety of mouse nerve tissues. We believe that the first kind of lipidomics study on HAAG species present in mammalian nerve tissue samples provided the foundation for future biological research in this unknown area.
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http://dx.doi.org/10.1016/j.aca.2020.07.016DOI Listing
September 2020

Peripheral serum metabolomic profiles inform central cognitive impairment.

Sci Rep 2020 08 20;10(1):14059. Epub 2020 Aug 20.

University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.

The incidence of Alzheimer's disease (AD) increases with age and is becoming a significant cause of worldwide morbidity and mortality. However, the metabolic perturbation behind the onset of AD remains unclear. In this study, we performed metabolite profiling in both brain (n = 109) and matching serum samples (n = 566) to identify differentially expressed metabolites and metabolic pathways associated with neuropathology and cognitive performance and to identify individuals at high risk of developing cognitive impairment. The abundances of 6 metabolites, glycolithocholate (GLCA), petroselinic acid, linoleic acid, myristic acid, palmitic acid, palmitoleic acid and the deoxycholate/cholate (DCA/CA) ratio, along with the dysregulation scores of 3 metabolic pathways, primary bile acid biosynthesis, fatty acid biosynthesis, and biosynthesis of unsaturated fatty acids showed significant differences across both brain and serum diagnostic groups (P-value < 0.05). Significant associations were observed between the levels of differential metabolites/pathways and cognitive performance, neurofibrillary tangles, and neuritic plaque burden. Metabolites abundances and personalized metabolic pathways scores were used to derive machine learning models, respectively, that could be used to differentiate cognitively impaired persons from those without cognitive impairment (median area under the receiver operating characteristic curve (AUC) = 0.772 for the metabolite level model; median AUC = 0.731 for the pathway level model). Utilizing these two models on the entire baseline control group, we identified those who experienced cognitive decline in the later years (AUC = 0.804, sensitivity = 0.722, specificity = 0.749 for the metabolite level model; AUC = 0.778, sensitivity = 0.633, specificity = 0.825 for the pathway level model) and demonstrated their pre-AD onset prediction potentials. Our study provides a proof-of-concept that it is possible to discriminate antecedent cognitive impairment in older adults before the onset of overt clinical symptoms using metabolomics. Our findings, if validated in future studies, could enable the earlier detection and intervention of cognitive impairment that may halt its progression.
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http://dx.doi.org/10.1038/s41598-020-70703-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441317PMC
August 2020

A Detergent-Free Method for Preparation of Lipid Rafts for the Shotgun Lipidomics Study.

Methods Mol Biol 2021 ;2187:27-35

Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Lipid rafts are microdomains on plasma membrane that contain high levels of cholesterol and sphingolipids. Because of the detergent-resistant property of lipid rafts, lipid rafts isolated by methods that use detergents frequently yield different results. Artifacts can also be introduced through the use of detergents. These limitations could be overcome with a detergent-free method which eliminates possible artificial influences. Importantly, lipid rafts prepared with a detergent-free method is more compatible to mass spectrometric analysis since the ion suppression effect is largely reduced.This chapter describes a detergent-free two-step method for preparation of lipid rafts. Firstly, a purified plasma membrane fraction is prepared from cells by sedimentation of the postnuclear supernatant (PNS) in a Percoll gradient. Secondly, the as-prepared plasma membranes are sonicated to release lipid rafts which are further isolated by flotation in a continuous gradient of Optiprep solution. Then, we introduce a typical shotgun lipidomics workflow that can be used as a cost-effective and relatively high throughput method to determine the lipidomes of lipid rafts.The method also makes an easy start for lipidomics studies.
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http://dx.doi.org/10.1007/978-1-0716-0814-2_2DOI Listing
March 2021

Circulating ethanolamine plasmalogen indices in Alzheimer's disease: Relation to diagnosis, cognition, and CSF tau.

Alzheimers Dement 2020 09 27;16(9):1234-1247. Epub 2020 Jul 27.

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Introduction: Altered lipid metabolism is implicated in Alzheimer's disease (AD), but the mechanisms remain obscure. Aging-related declines in circulating plasmalogens containing omega-3 fatty acids may increase AD risk by reducing plasmalogen availability.

Methods: We measured four ethanolamine plasmalogens (PlsEtns) and four closely related phosphatidylethanolamines (PtdEtns) from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 1547 serum) and University of Pennsylvania (UPenn; n = 112 plasma) cohorts, and derived indices reflecting PlsEtn and PtdEtn metabolism: PL-PX (PlsEtns), PL/PE (PlsEtn/PtdEtn ratios), and PBV (plasmalogen biosynthesis value; a composite index). We tested associations with baseline diagnosis, cognition, and cerebrospinal fluid (CSF) AD biomarkers.

Results: Results revealed statistically significant negative relationships in ADNI between AD versus CN with PL-PX (P = 0.007) and PBV (P = 0.005), late mild cognitive impairment (LMCI) versus cognitively normal (CN) with PL-PX (P = 2.89 × 10 ) and PBV (P = 1.99 × 10 ), and AD versus LMCI with PL/PE (P = 1.85 × 10 ). In the UPenn cohort, AD versus CN diagnosis associated negatively with PL/PE (P = 0.0191) and PBV (P = 0.0296). In ADNI, cognition was negatively associated with plasmalogen indices, including Alzheimer's Disease Assessment Scale 13-item cognitive subscale (ADAS-Cog13; PL-PX: P = 3.24 × 10 ; PBV: P = 6.92 × 10 ) and Mini-Mental State Examination (MMSE; PL-PX: P = 1.28 × 10 ; PBV: P = 6.50 × 10 ). In the UPenn cohort, there was a trend toward a similar relationship of MMSE with PL/PE (P = 0.0949). In ADNI, CSF total-tau was negatively associated with PL-PX (P = 5.55 × 10 ) and PBV (P = 7.77 × 10 ). Additionally, CSF t-tau/Aβ ratio was negatively associated with these same indices (PL-PX, P = 2.73 × 10 ; PBV, P = 4.39 × 10 ). In the UPenn cohort, PL/PE was negatively associated with CSF total-tau (P = 0.031) and t-tau/Aβ (P = 0.021). CSF Aβ was not significantly associated with any of these indices in either cohort.

Discussion: These data extend previous studies by showing an association of decreased plasmalogen indices with AD, mild cognitive impairment (MCI), cognition, and CSF tau. Future studies are needed to better define mechanistic relationships, and to test the effects of interventions designed to replete serum plasmalogens.
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http://dx.doi.org/10.1002/alz.12110DOI Listing
September 2020

Analytical challenges of shotgun lipidomics at different resolution of measurements.

Trends Analyt Chem 2019 Dec 17;121. Epub 2019 Oct 17.

Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229 USA.

The essence of shotgun lipidomics is to maintain consistency of the chemical environment of lipid samples during mass spectrometry acquisition. This strategy is suitable for large-scale quantitative analysis. This strategy also allows sufficient time to collect data to improve the signal-to-noise ratio. The initial approach of shotgun lipidomics was the electrospray ionization (ESI)-based direct infusion mass spectrometry strategy. With development of mass spectrometry for small molecules, shotgun lipidomics methods have been extended to matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) and ambient mass spectrometry, including MS imaging methods. Furthermore, the object of analysis has extended from organ and body fluid levels to tissue and cell levels with technological developments. In this article, we summarize the status and technical challenges of shotgun lipidomics at different resolution of measurements from the mass spectrometry perspective.
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http://dx.doi.org/10.1016/j.trac.2019.115697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382544PMC
December 2019

The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats.

Commun Biol 2020 Jul 17;3(1):389. Epub 2020 Jul 17.

Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Mitochondrial dysfunction contributes to cardiac pathologies. Barriers to new therapies include an incomplete understanding of underlying molecular culprits and a lack of effective mitochondria-targeted medicines. Here, we test the hypothesis that the cardiolipin-binding peptide elamipretide, a clinical-stage compound under investigation for diseases of mitochondrial dysfunction, mitigates impairments in mitochondrial structure-function observed after rat cardiac ischemia-reperfusion. Respirometry with permeabilized ventricular fibers indicates that ischemia-reperfusion induced decrements in the activity of complexes I, II, and IV are alleviated with elamipretide. Serial block face scanning electron microscopy used to create 3D reconstructions of cristae ultrastructure reveals that disease-induced fragmentation of cristae networks are improved with elamipretide. Mass spectrometry shows elamipretide did not protect against the reduction of cardiolipin concentration after ischemia-reperfusion. Finally, elamipretide improves biophysical properties of biomimetic membranes by aggregating cardiolipin. The data suggest mitochondrial structure-function are interdependent and demonstrate elamipretide targets mitochondrial membranes to sustain cristae networks and improve bioenergetic function.
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http://dx.doi.org/10.1038/s42003-020-1101-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368046PMC
July 2020

Novel strategies for enhancing shotgun lipidomics for comprehensive analysis of cellular lipidomes.

Trends Analyt Chem 2019 Nov 27;120. Epub 2018 Nov 27.

College of Basic Medical Sciences, Zhejiang Chinese Medical University, 548 Bingwen Road, Hangzhou, Zhejiang 310053, China.

Shotgun lipidomics is one of the most powerful tools in analysis of cellular lipidomes in lipidomics, which directly analyzes lipids from lipid extracts of diverse biological samples with high accuracy/precision. However, despite its great advances in high throughput analysis of cellular lipidomes, low coverage of poorly ionized lipids, especially those species in very low abundance, and some types of isomers within complex lipid extracts by shotgun lipidomics remains a huge challenge. In the past few years, many strategies have been developed to enhance shotgun lipidomics for comprehensive analysis of lipid species. Chemical derivatization represents one of the most attractive and effective strategies, already receiving considerable attention. This review focuses on novel advanced derivatization strategies for enhancing shotgun lipidomics. It is anticipated that with the development of enhanced strategies, shotgun lipidomics can make greater contributions to biological and biomedical research.
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http://dx.doi.org/10.1016/j.trac.2018.11.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344273PMC
November 2019

Perioperative and oncological outcomes following minimally invasive versus open pancreaticoduodenectomy for pancreatic duct adenocarcinoma.

Surg Endosc 2020 Jul 6. Epub 2020 Jul 6.

Department of General Surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China.

Background: The outcomes of minimally invasive pancreaticoduodenectomy have not been adequately compared with those of open pancreaticoduodenectomy in patients with pancreatic ductal adenocarcinoma. We performed a meta-analysis to compare the perioperative and oncological outcomes of these two pancreaticoduodenectomy procedures specifically in patients with pancreatic ductal adenocarcinoma.

Methods: Before this study was initiated, a specific protocol was designed and has been registered in PROSEPRO (ID: CRD42020149438). Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, PubMed, EMBASE, Web of Science, Cochrane Central Register, and ClinicalTrials.gov databases were systematically searched for studies published between January 1994 and October 2019. Overall survival, disease-free survival, and time to commencing adjuvant chemotherapy were the primary endpoint measurements, whereas perioperative and short-term outcomes were the secondary endpoints.

Results: The final analysis included 9 retrospective cohorts comprising 11,242 patients (1377 who underwent minimally invasive pancreaticoduodenectomy and 9865 who underwent open pancreaticoduodenectomy). There were no significant differences in the patients' overall survival, operative time, postoperative complications, 30-day mortality, rate of vein resection, number of harvested lymph nodes, or rate of positive lymph nodes between the two approaches. However, disease-free survival, time to starting adjuvant chemotherapy, length of hospital stay, and rate of negative margins in patients who underwent minimally invasive pancreaticoduodenectomy showed improvements relative to those in patients who underwent open surgery.

Conclusions: Minimally invasive pancreaticoduodenectomy provides similar or even improved perioperative, short-term, and long-term oncological outcomes when compared with open pancreaticoduodenectomy for patients with pancreatic ductal adenocarcinoma.
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http://dx.doi.org/10.1007/s00464-020-07641-1DOI Listing
July 2020

Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress.

Cell Metab 2020 Aug 18;32(2):229-242.e8. Epub 2020 Jun 18.

Department of Radiation Oncology, James Comprehensive Cancer Center and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, James Comprehensive Cancer Center at The Ohio State University, Columbus, OH 43210, USA. Electronic address:

Glioblastoma (GBM), a mostly lethal brain tumor, acquires large amounts of free fatty acids (FAs) to promote cell growth. But how the cancer avoids lipotoxicity is unknown. Here, we identify that GBM upregulates diacylglycerol-acyltransferase 1 (DGAT1) to store excess FAs into triglycerides and lipid droplets. Inhibiting DGAT1 disrupted lipid homeostasis and resulted in excessive FAs moving into mitochondria for oxidation, leading to the generation of high levels of reactive oxygen species (ROS), mitochondrial damage, cytochrome c release, and apoptosis. Adding N-acetyl-cysteine or inhibiting FA shuttling into mitochondria decreased ROS and cell death induced by DGAT1 inhibition. We show in xenograft models that targeting DGAT1 blocked lipid droplet formation, induced tumor cell apoptosis, and markedly suppressed GBM growth. Together, our study demonstrates that DGAT1 upregulation protects GBM from oxidative damage and maintains lipid homeostasis by facilitating storage of excess FAs. Targeting DGAT1 could be a promising therapeutic approach for GBM.
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http://dx.doi.org/10.1016/j.cmet.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415721PMC
August 2020

New-Onset Diabetes Mellitus After Distal Pancreatectomy: A Systematic Review and Meta-Analysis.

J Laparoendosc Adv Surg Tech A 2020 Nov 18;30(11):1215-1222. Epub 2020 Jun 18.

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Endocrine insufficiency must be considered following distal pancreatectomy (DP), because diabetes mellitus can impose a long-term burden on patients. This systematic review and meta-analysis aimed to identify the incidence and severity of new-onset diabetes mellitus (NODM) after DP for benign and malignant tumors, and other indications. Articles reporting NODM after DP from PubMed, Embase, Cochrane Library, and Google Scholar were analyzed. The quality of the studies was assessed using the Newcastle-Ottawa Scale or MOGA scale. Inverse variance analysis calculated the overall NODM incidence, and 95% confidence intervals (CIs) and values were determined. Subgroup analyses considered pre-existing pancreatic diseases. The quantitative analysis involved 18 articles that described 2356 patients with pancreatic neoplasms or inflammatory lesions. The overall incidence of NODM after DP was 29% (95% CI 25-33). The NODM rates were 23% (95% CI 17-30) and 38% (95% CI 30-45) for patients with pancreatic neoplasms and chronic pancreatitis, respectively. Pre-existing chronic pancreatitis and being male were risks associated with NODM. NODM is fairly common after DP. Surgeons and patients should be aware of postoperative treatment-dependent endocrine dysfunction. Larger cohort studies are required to clarify the risk factors for NODM after DP.
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http://dx.doi.org/10.1089/lap.2020.0090DOI Listing
November 2020